Current Drug Metabolism - Volume 19, Issue 4, 2018

Background: Over the past two decades, saccharolactone has been routinely used in in vitro microsomal incubations, and sometimes in incubations with recombinant Uridine diphosphoglucuronosyl transferases (UGT) while investigating glucuronidation reactions. The addition of saccharolactone is aimed at completely inhibiting β- glucuronidases that may be present in the microsomes, in the anticipation of accurate identification and quantification of the formed glucuronide metabolites. Recent research has demonstrated that saccharolatone may not serve the intended objective, and may even lead to inhibition of certain UGTs. Objective: This report investigates the historic evidence in the practice of saccharolactone addition in relation to - glucuronidases and UGTs. The chemical nature and inhibition potency of saccharolactone are explored in an attempt to unravel the myth in its application. Finally, the collective evidence is discussed in an effort to provide guidance to drug metabolism scientists on the utilization of saccharolactone. Conclusion: In-depth evaluation of the experimental evidence in the literature points toward a weak rationale for general in vitro application of saccharolactone. Furthermore, inhibition of recombinant or microsomal UGTs by saccharolactone may be model dependent. Overall, the integrated data suggests that saccharolactone should not be utilized in in vitro microsomal incubations with the objective of inhibiting β-glucuronidases.

Background: Renal proximal tubule (PT) epithelial cells, expressing uptake and efflux transporters at basolateral and apical membranes, are the location of active renal drug secretion and reabsorption. In addition to singly transfected cells, an in vitro renal cell-based model is a requirement to study the active renal secretion of drugs, drug-drug interactions (DDIs), drug-induced kidney injury, nephrotoxicity holistically and potentially renal replacement therapies. Objectives: So far, two-dimensional (2D) cell culture of primary and immortalized PT cells has been the only tool to study drugs active secretion, interactions and nephrotoxicity, however a number of in vivo characteristics of cells such as drug transporter expression and function, along with morphological features are lost during in vitro cell culture. Cellular microenvironment, extracellular matrix, cell-cell interactions, microfluidic environment and tubular architecture are the factors lacking in 2D cell culture. Currently, there are a few 3D cell culture platforms mimicking the in vivo conditions of PT cells and thus potentially enabling the necessary factors for the full functional PT cells. Conclusion: In this review, we address in vivo physiological and morphological characteristics of PT cells, comparing their available sources and remaining in vivo features. In addition, 2D and 3D cell culture platforms and the influence of cell culture architecture on the physiological characteristics of cells are reviewed. Finally, future perspective of 3D models, kidney and multi organs on a chip, generation of kidney organoids, other ex vivo renal models and their capabilities to study drug disposition and in vitro-in vivo extrapolation are described.

Background: Medical application of nanotechnology is termed as Nanomedicine and is widely used in healthcare industries. Nanotechnology has helped Physicians, Scientists and Technologists to understand the changes in cellular levels to develop nanomedicines and address the challenges faced by the healthcare sectors. Nanoparticles with less than 1nm in size have been used as drug delivery and gene delivery systems to accelerate the drug action in humans. Size of nanomaterials is akin to that of biomolecules and expected to have better interactions. Hence, its utility for various biomedical applications is explored. Objective: Pharmacokinetics, metabolism, permeability, distribution and elimination studies of nanoparticles are essential to understand its potency, toxicity threshold and confirm its safe use in humans. Reports were available for toxicity studies on nanoparticles, but work on metabolism, pharmacokinetics, distribution and permeability of nanomedicine is limited. Hence, the main focus of this review article is about metabolism, pharmacokinetics, permeability and biodistribution of nanomaterials used in nanomedicine. Conclusion: Nanomedicine is increasingly becoming important in the treatment of diseases and diagnosis. Size of the particle plays an important role. As the particle size decreases its effect to cure the disease increases. Pharmacokinetics, bioavailability, half-life, metabolism, biodistribution and permeability of nanomedicine were found to be better than that of microsized drugs. In vitro and In vivo ADME (Absorption, Distribution, Metabolism and Excretion) studies are mandatory for pharmaceutical organic drugs. Similarly, nanomaterials should be subjected to both in vitro and in vivo ADME studies. Thus, nanomedicine can assist in the development of safe personalized medicine in humans.

Background: Non-Small Cell Lung Carcinoma is one of the major cause of morbidity and mortality worldwide with an incidence rate of 1.3 million cases per year. Heat shock protein 90 (HSP90) is a promising drug target in cancer treatment. HSP90 is required to activate numerous eukaryotic proto-oncogenic protein kinases, hence play a prominent role in cancer. Method: We reviewed fifty-five articles to highlight the importance of HSP90 in NSCLC and the recent developments of its inhibitors. Results: This review showed that HSP90 inhibitors i.e. Ganestespib have shown great potential in the treatment of non-small cell lung carcinoma (NSCLC). Different HSP90 inhibitors has been designed till date that acts as effective drugs in tumour suppression. However, the utility of these drugs has been limited due to several drawbacks including hepato-toxicity, poor solubility, and poorly tolerated formulations. Conclusion: The goal of this review is to present the data in support of use of HSP90 inhibitors in NSCLC and to provide an overview of the on-going clinical trials involving new-generation HSP90 inhibitors.

Background: The calcineurin inhibitor tacrolimus (Tac) is an integral part of the standard immunosuppressive regimen after renal transplantation (RTx). However, clinical management of Tac therapy can be challenging because of its narrow therapeutic window and because many factors interfere with its metabolism. Therefore, therapeutic drug monitoring is used to adjust the dosage. Method: Recently, we were able to classify patients receiving tacrolimus into two major metabolism groups by simple calculation of the C/D ratio (expressed as the blood concentration normalized by the dose). Results: We showed that the C/D ratio is significantly associated with the (renal) outcome of recipients after kidney and liver transplantation. Conclusion: These findings are interesting and relevant to transplant physicians and physicians interested in immunosuppressive therapy. We therefore review current state of the art aspects of tacrolimus pharmacokinetics including genetics or different tacrolimus formulations (twice-daily immediate-release tacrolimus capsules, once-daily extended- release tacrolimus capsules; novel once-daily tacrolimus tablets) and their possible clinical impact including practical considerations for clinicians.

Background: Hibiscus sabdariffa, Lippia citriodora, Rosmarinus officinalis and Olea europaea, are rich in bioactive compounds that represent most of the phenolic compounds' families and have exhibited potential benefits in human health. These plants have been used in folk medicine for their potential therapeutic properties in human chronic diseases. Recent evidence leads to postulate that polyphenols may account for such effects. Nevertheless, the compounds or metabolites that are responsible for reaching the molecular targets are unknown. Objective: data based on studies directly using complex extracts on cellular models, without considering metabolic aspects, have limited applicability. In contrast, studies exploring the absorption process, metabolites in the blood circulation and tissues have become essential to identify the intracellular final effectors that are responsible for extracts bioactivity. Once the cellular metabolites are identified using high-resolution mass spectrometry, docking techniques suppose a unique tool for virtually screening a large number of compounds on selected targets in order to elucidate their potential mechanisms. Results: we provide an updated overview of the in vitro and in vivo studies on the toxicity, absorption, permeability, pharmacokinetics and cellular metabolism of bioactive compounds derived from the abovementioned plants to identify the potential compounds that are responsible for the observed health effects. Conclusion: we propose the use of targeted metabolomics followed by in silico studies to virtually screen identified metabolites on selected protein targets, in combination with the use of the candidate metabolites in cellular models, as the methods of choice for elucidating the molecular mechanisms of these compounds.

Background: Inter-individual variability in hepatic drug metabolizing enzyme (DME) activity is a major contributor to heterogeneity in drug clearance and safety. Accurate data on expression levels and activities of DMEs is an important prerequisite for in vitro-in vivo extrapolation and in silico based predictions. Characterization and assessment of inter-correlations of the major DMEs cytochrome P450s (CYPs) and UDP-glucuronosyltransferases (UGTs) have been extensively documented, but simultaneous quantification including other major DMEs has been lacking. Objective: Assessment of inter-donor variability and inter-correlations of CYPs, UGTs, sulfotransferases (SULTs), glutathione S-transferases (GSTs), NAD(P)H:quinone oxidoreductase 1 (NQO1) and NRH: quinone oxidoreductase 2 (NQO2) in a set of 20 individual liver homogenates. Method: The main drug metabolizing isoforms of CYP and UGT have been reaction phenotype in individual liver microsomes and NQO1, NQO2, GSTT1 and GSTT2 in corresponding cytosol. In addition, we assessed overall SULT activity in liver cytosol using acetaminophen and 7-hydroxycoumarin as non-selective substrates and cytosolic GST activity using the non-selective substrate 1-chloro-2,4-dinitrobenzene (CDNB). Expression of GST isoforms was also assessed. Results and Conclusion: While hepatic NQO1 activity was highly variable, NQO2 activity was more conserved. In addition, we found that of the hepatic GST isoforms, the variation in GSTM3 levels, which is poorly studied, was highest. The majority of significant correlations were found amongst CYP and UGT enzyme activities. The dataset presented provides the absolute quantification of the largest number of hepatic DME activities so far and constitute an essential resource for in silico toxicokinetic and metabolic modelling studies.